Reduced-Dose Versus Full-Dose Alteplase for High-Risk Pulmonary Embolism

NCT07816978 | Not Yet Recruiting Phase 4 DMC

• 2 other identifiers: REDSTEM2024-515904-37-00
• Study Type: interventional
• Target: 400
• Locations: 3 countries
• Sites: 23

Brief Summary

High-risk pulmonary embolism is a life-threatening condition requiring immediate reperfusion therapy. Full-dose systemic thrombolysis is recommended as first-line treatment, but its use is limited by the risk of major bleeding, including intracranial hemorrhage. Reduced-dose systemic thrombolysis may reduce bleeding while maintaining clinical efficacy, but this strategy has not been adequately evaluated in patients with high-risk pulmonary embolism. REDSTEM is an international, multicenter, randomized, adaptive, open-label, blinded-endpoint phase 4 trial comparing reduced-dose alteplase with standard full-dose alteplase in adults with acute high-risk pulmonary embolism. The trial will assess whether reduced-dose alteplase preserves early clinical efficacy while reducing severe clinically significant bleeding. Participants will be followed for up to 12 months.

Conditions

Pulmonary Embolism Acute

Keywords

Systemic thrombolysis; Efficacy; Safety; Reduced-dose; Alteplase

Outcome Measures

Primary Outcomes (2)

• Incidence of composite efficacy endpoint

  Incidence of a composite endpoint comprising all-cause mortality within 7 days, cardiopulmonary resuscitation and/or veno-arterial extracorporeal membrane oxygenation within 7 days, recurrent pulmonary embolism within 7 days, clinical deterioration within 24 hours, and lack of clinical improvement at 6 hours.

  Within 7 days after randomization

• Key secondary endpoint - Incidence of severe clinically significant bleeding

  Incidence of severe clinically significant bleeding, defined as major bleeding according to International Society on Thrombosis and Haemostasis criteria or bleeding requiring urgent medical intervention.

  Within 7 days after randomization

Secondary Outcomes (16)

• All-cause mortality

  At 7 days and 30 days after randomization

• Pulmonary embolism-related mortality

  At 7 days and 30 days after randomization

• Cardiopulmonary resuscitation and/or VA-ECMO

  Within 7 days after randomization

• Incidence of clinical deterioration

  Within 24 hours after randomization

• Lack of clinical improvement assessed by SCAI SHOCK stage and oxygen requirement

  At 6 hours after randomization

Other Outcomes (10)

• All-cause mortality at 12 months

  At 12 months after randomization

• At 12 months after randomization

  At 12 months after randomization

• Persistent dyspnea assessed using the modified Medical Research Council scale

  At 3 months and 12 months after randomization

Study Arms (2)

Reduced-Dose Alteplase

EXPERIMENTAL

Participants randomized to reduced-dose systemic thrombolysis will receive alteplase 0.6 mg/kg body weight, up to a maximum dose of 50 mg, administered intravenously over 15 minutes.

Drug: Reduced-dose alteplase

Full-Dose Alteplase

ACTIVE COMPARATOR

Participants randomized to standard full-dose systemic thrombolysis will receive alteplase 1.5 mg/kg body weight, up to a maximum dose of 100 mg, administered as a 10 mg intravenous bolus over 1 to 2 minutes followed by a 90 mg intravenous infusion over 2 hours.

Drug: Full-dose alteplase

Interventions

Reduced-dose alteplase DRUG

Alteplase 0.6 mg/kg body weight, maximum 50 mg, administered as an intravenous infusion over 15 minutes

Also known as: Reduced-dose systemic thrombolysis, Low-dose alteplase, tPA

Reduced-Dose Alteplase

Full-dose alteplase DRUG

Alteplase 1.5 mg/kg body weight, maximum 100 mg, administered as a 10 mg intravenous bolus over 1 to 2 minutes followed by 90 mg as an intravenous infusion over 2 hours.

Also known as: Full-dose systemic thrombolysis, Standard-dose alteplase, tPA

Full-Dose Alteplase

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participant aged 18 years or older.
• Acute pulmonary embolism verified by computed tomography pulmonary angiography or pulmonary angiography. In hemodynamically unstable participants unable to undergo immediate imaging, presumed pulmonary embolism may be diagnosed based on bedside echocardiographic findings consistent with acute right ventricular pressure overload and high clinical suspicion of pulmonary embolism, provided that alternative causes of hemodynamic instability have been reasonably excluded. In such cases, the treating clinician must have independently decided to initiate thrombolytic therapy irrespective of study participation, and confirmatory imaging demonstrating pulmonary embolism must be performed as soon as clinically feasible.
• High risk for early death, defined by at least one of the following:
• High-risk pulmonary embolism according to European Society of Cardiology criteria:
• Cardiac arrest with return of spontaneous circulation;
• Obstructive shock, defined as systolic blood pressure \<90 mmHg or use of vasopressors to maintain systolic blood pressure ≥90 mmHg despite adequate filling status, together with end-organ hypoperfusion such as elevated serum lactate \>2 mmol/L, altered mental status, or cold clammy skin;
• Persistent hypotension, defined as systolic blood pressure \<90 mmHg or a drop in systolic blood pressure ≥40 mmHg for longer than 15 minutes, not caused by new-onset arrhythmia, hypovolemia, or sepsis.
• Abnormal right ventricular function on echocardiography or computed tomography pulmonary angiography, defined as right ventricular/left ventricular ratio ≥1.0, and elevated cardiac troponin above the local upper reference limit, and acute respiratory failure not primarily caused by underlying lung disease, defined as requiring facemask oxygen supplementation ≥12 L/min, high-flow nasal oxygen, or non-invasive ventilation with FiO2 ≥60% to reach oxygen saturation ≥94%.
• Female participants of childbearing potential must have a negative urine or serum pregnancy test.

You may not qualify if:

• Catastrophic pulmonary embolism, defined as ongoing cardiac arrest and/or need for extracorporeal cardiopulmonary resuscitation and/or immediate VA-ECMO as judged by the treating physicians.
• Known hypersensitivity to alteplase or any of its excipients.
• Contraindication to systemic thrombolysis with one or more of the following:
• History of hemorrhagic stroke;
• Ischemic stroke within the previous 6 months;
• Central nervous system neoplasm;
• Major trauma, major surgery, or major head injury within the previous 3 weeks;
• Active life-threatening bleeding, bleeding into a critical organ or area, or known severe bleeding diathesis;
• Chronic use of full-dose oral or parenteral anticoagulation before presentation.
• The participant has already received reperfusion treatment for the index pulmonary embolism before randomization, including systemic thrombolysis, surgical embolectomy, or catheter-directed intervention.
• Pregnancy.
• Current participation in another study that would interfere with participation in this trial.
• Any other condition that would put the participant at unacceptable risk from the trial interventions as judged by the treating clinician.
• In countries where required by national regulations: lack of affiliation to a social security system or equivalent health insurance coverage.

Sponsors & Collaborators

• Sahlgrenska University Hospital: lead
• Göteborg University: collaborator
• Leiden University Medical Center: collaborator
• Assistance Publique - Hôpitaux de Paris: collaborator
• Rigshospitalet, Denmark: collaborator
• University Hospital, Akershus: collaborator
• University of Zurich: collaborator

Study Sites (23)

Rigshospitalet

Copenhagen, Denmark

Location

Haukeland University Hospital

Bergen, 5021, Norway

Location

Drammen Hospital

Drammen, 3004, Norway

Location

Ostfold Hisptal

Grålum, 1714, Norway

Location

Akershus University Hospital

Lörenskog, 1478, Norway

Location

Oslo University Hospital, Ullevål

Oslo, 0450, Norway

Location

Stavanger University Hospital

Stavanger, 4021, Norway

Location

Sahlgrenska University Hospital

Gothenburg, Västra Götaland County, 413 45, Sweden

Location

Falun Hospital

Falun, Sweden

Location

Sahlgrenska University Hospital/Östra

Gothenburg, Sweden

Location

Ryhov County Hospital

Jönköping, Sweden

Location

Skåne University Hospital, Lund

Lund, Sweden

Location

Skåne University Hospital, Malmö

Malmö, Sweden

Location

Sahlgrenska University Hospital/Mölndal

Mölndal, Sweden

Location

Norrtälje Hospital

Norrtälje, Sweden

Location

Skaraborgs Hospital Skövde

Skövde, Sweden

Location

Capio S:t Göran's Hospital

Stockholm, Sweden

Location

Danderyd Hospital

Stockholm, Sweden

Location

Karolinska University Hospital, Huddinge

Stockholm, Sweden

Location

Karolinska University Hospital, Solna

Stockholm, Sweden

Location

Södersjukhuset, Stockholm South General Hospital

Stockholm, Sweden

Location

University Hospital of Umeå

Umeå, Sweden

Location

Uppsala University Hospital

Uppsala, Sweden

Location

Related Publications (10)

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  PMID: 31504429 BACKGROUND

• Stevens SM, Woller SC, Kreuziger LB, Bounameaux H, Doerschug K, Geersing GJ, Huisman MV, Kearon C, King CS, Knighton AJ, Lake E, Murin S, Vintch JRE, Wells PS, Moores LK. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest. 2021 Dec;160(6):e545-e608. doi: 10.1016/j.chest.2021.07.055. Epub 2021 Aug 2.

  PMID: 34352278 BACKGROUND

• Silver MJ, Giri J, Duffy A, Jaber WA, Khandhar S, Ouriel K, Toma C, Tu T, Horowitz JM. Incidence of Mortality and Complications in High-Risk Pulmonary Embolism: A Systematic Review and Meta-Analysis. J Soc Cardiovasc Angiogr Interv. 2023 Jan 27;2(1):100548. doi: 10.1016/j.jscai.2022.100548. eCollection 2023 Jan-Feb.

  PMID: 39132523 BACKGROUND

• Keller K, Hobohm L, Ebner M, Kresoja KP, Munzel T, Konstantinides SV, Lankeit M. Trends in thrombolytic treatment and outcomes of acute pulmonary embolism in Germany. Eur Heart J. 2020 Jan 21;41(4):522-529. doi: 10.1093/eurheartj/ehz236.

  PMID: 31102407 BACKGROUND

• Wang C, Zhai Z, Yang Y, Wu Q, Cheng Z, Liang L, Dai H, Huang K, Lu W, Zhang Z, Cheng X, Shen YH; China Venous Thromboembolism (VTE) Study Group. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest. 2010 Feb;137(2):254-62. doi: 10.1378/chest.09-0765. Epub 2009 Sep 9.

  PMID: 19741062 BACKGROUND

• Goldhaber SZ, Agnelli G, Levine MN. Reduced dose bolus alteplase vs conventional alteplase infusion for pulmonary embolism thrombolysis. An international multicenter randomized trial. The Bolus Alteplase Pulmonary Embolism Group. Chest. 1994 Sep;106(3):718-24. doi: 10.1378/chest.106.3.718.

  PMID: 8082347 BACKGROUND

• Melamed R, Tierney DM, Xia R, Brown CS, Mara KC, Lillyblad M, Sidebottom A, Wiley BM, Khapov I, Gajic O. Safety and Efficacy of Reduced-Dose Versus Full-Dose Alteplase for Acute Pulmonary Embolism: A Multicenter Observational Comparative Effectiveness Study. Crit Care Med. 2024 May 1;52(5):729-742. doi: 10.1097/CCM.0000000000006162. Epub 2024 Jan 3.

  PMID: 38165776 BACKGROUND

• Sanchez O, Charles-Nelson A, Ageno W, Barco S, Binder H, Chatellier G, Duerschmied D, Empen K, Ferreira M, Girard P, Huisman MV, Jimenez D, Katsahian S, Kozak M, Lankeit M, Meneveau N, Pruszczyk P, Petris A, Righini M, Rosenkranz S, Schellong S, Stefanovic B, Verhamme P, de Wit K, Vicaut E, Zirlik A, Konstantinides SV, Meyer G; PEITHO-3 Investigators. Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial. Thromb Haemost. 2022 May;122(5):857-866. doi: 10.1055/a-1653-4699. Epub 2021 Oct 31.

  PMID: 34560806 BACKGROUND

• Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.

  PMID: 15842354 BACKGROUND

• Stadlbauer A, Verbelen T, Binzenhofer L, Goslar T, Supady A, Spieth PM, Noc M, Verstraete A, Hoffmann S, Schomaker M, Hopler J, Kraft M, Tautz E, Hoyer D, Tongers J, Haertel F, El-Essawi A, Salem M, Rangel RH, Hullermann C, Kriz M, Schrage B, Moises J, Sabate M, Pappalardo F, Crusius L, Mangner N, Adler C, Tichelbacker T, Skurk C, Jung C, Kufner S, Graf T, Scherer C, Villegas Sierra L, Billig H, Majunke N, Speidl WS, Zilberszac R, Chiscano-Camon L, Uribarri A, Riera J, Roncon-Albuquerque R Jr, Terauda E, Erglis A, Tavazzi G, Zeymer U, Knorr M, Kilo J, Mobius-Winkler S, Schwinger RHG, Frank D, Borst O, Haberle H, De Roeck F, Vrints C, Schmid C, Nickenig G, Hagl C, Massberg S, Schafer A, Westermann D, Zimmer S, Combes A, Camboni D, Thiele H, Lusebrink E; High-risk P. E. Investigator Group. Management of high-risk acute pulmonary embolism: an emulated target trial analysis. Intensive Care Med. 2025 Mar;51(3):490-505. doi: 10.1007/s00134-025-07805-4. Epub 2025 Feb 25.

  PMID: 39998658 BACKGROUND

MeSH Terms

Interventions

Tissue Plasminogen Activator

Intervention Hierarchy (Ancestors)

Serine Endopeptidases; Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Serine Proteases; Plasminogen Activators; Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Biological Factors

Study Officials

• Kristina Svennerholm

  Sahlgrenska University Hospital / University of Gothenburg

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kristina Svennerholm, MD PhD

CONTACT

+46313421000; kristina.svennerholm@vgregion.se

Annika Odenstedt, Coordinator

CONTACT

+46313421000; annika.odenstedt@vgregion.se

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The trial is open-label because alteplase dose and administration regimen differ between treatment groups and immediate clinical management requires knowledge of treatment allocation. The primary endpoint and key secondary endpoint will be adjudicated by an independent central Critical Events Committee blinded to treatment allocation. The trial statistician responsible for the final analyses will remain blinded until database lock and completion of all prespecified analyses
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Model Details: Participants will be randomized in a 1:1 ratio to reduced-dose alteplase or standard full-dose alteplase.

Study Record Dates

• First Submitted: September 2, 2026
• First Posted: September 14, 2026
• Study Start (Estimated): December 1, 2026
• Primary Completion (Estimated): January 31, 2030
• Study Completion (Estimated): January 31, 2031
• Last Updated: September 17, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: After publication of the trial results.
• Access Criteria: Reasonable request, subject to approval by the sponsor and principal investigator and applicable legal, ethical, and data protection requirements.

Locations

NO (6); DK (1); SE (16)